Not Applicable
This invention relates generally to a method of treating hyperproliferative prostatic diseases, and in particular, to the use of active forms of vitamin D to inhibit the hyperproliferative cellular activity of these diseases and to promote differentiation of the cells.
The prostate gland is found exclusively in male mammals and is subject to certain hyperproliferative diseases. A proliferation of basal and stroma cells of the prostate gland gives rise to benign prostatic hyperplasia which is one common prostate disease. Another common prostate disease is prostate cancer, especially prostatic adenocarcinoma. Adenocarcinoma of the prostate is the most common of the fatal pathophysiological prostate cancers, and typically involves a malignant transformation of epithelial cells in the peripheral region of the prostate gland. Both prostatic hyperplasia and prostate cancer have a high rate of incidence in the aging human male population. Approximately one out of every four males above the age of 55 suffers from a prostate disease of some form or another.
Prostate cancer is currently the second most frequent cause of cancer death after lung cancer among American males. Mortality rates for prostate cancer increase logarithmically with age and are two times higher in U.S. blacks than whites. Internationally, mortality rates are highest in U.S. blacks and in northern Europe and are lowest in Japan. It is projected that by the year 2000, a 90% increase in annual incidence of the disease and a 37% increase in annual mortality rates will be observed. Although prostate cancer may be a relatively indolent neoplasm in the elderly, the overall decrease in life span in patients with this disease is approximately 10 years.
Improvement in the treatment of prostate cancer has centered on early detection. In recent years, screening tests which detect certain proteins or peptides secreted by the prostate gland, i.e., markers, (e.g, prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostatic inhibin (PIP)), have increased the power to diagnose this disease in asymptomatic patients.
Treatment of prostate cancer in men under the age of 65 has focused on radical surgery, e.g., prostatectomy, and/or radiotherapy, but the impact of these aggressive approaches on overall survival remains debatable. The approach to treatment of men over the age of 65 historically has been more conservative, and is based on the ablation or control of testosterone production. Such ablation or control is usually achieved by surgical castration, by administration of pituitary gonadotropin inhibitors such as estrogens or luteinizing hormone releasing hormone (LHRH) analogues, or a combination of these treatment methods. Estrogens, such as diethylstilbestrol, are potent inhibitors of the release from the pituitary gland of luteinizing hormone (LH), the gonadotropin that regulates testosterone production, and consequently, estrogen administration can cause a fall in testosterone to castration levels. Maximum suppression of plasma testosterone is typically achieved by a dosage of 3 mg/day of diethylstilbestrol. Other estrogens such as conjugated estrogens are about as equally effective in the lowering of the plasma level as diethylstilbestrol. However, diethylstilbestrol has a poor cardiovascular profile, and death from cardiovascular disease is not uncommon in patients treated with large doses of diethylstilbestrol. Thus, while dosages of up to 3 mg/day of diethylstilbestrol are typically safe, this treatment regime is not indicated for men with preexisting cardiovascular disease.
Prostatic carcinoma often metastasizes to the pelvis and lumbar vertebrae, causing bone loss and associated pain. Hormone manipulation often may result in significant palliation of metastatic prostate cancer, with improvement of bone pain and other disease-associated symptoms. Androgen ablation is, thus, also a major adjunctive therapy in advanced metastatic prostate cancer.
Despite initial improvement on hormonal treatment, a majority of patients with locally unresectable or metastatic disease will eventually fail to respond to further hormonal therapies. A recent study suggests that human prostate cancer cells may cycle between being androgen-independent and androgen-dependent. Such cycling may account for the return of the cancer after initial improvement. In this large group of patients, other forms of treatment, unfortunately, are far less effective. Radiotherapy often may relieve the symptoms of bone pain, but is not curative. Over time, the disease will progress with a fatal outcome.
As noted hereinabove, prostatic hyperplasia is another common hyperproliferative disease of the prostate gland. The disorder affects men over the age of 45 and increases in frequency with age. Prostatic hyperplasia begins in the periurethral region as a localized proliferation and progresses to compress the remaining normal gland. The hyperplasia can compress and obstruct the urethra. Treatment includes surgery, and administration of pituitary gonadotropin inhibitors and/or 5xcex1-reductase enzyme inhibitors.
In another area of physiology and biochemistry, the vitamin D area, extensive research during the past two decades has established important biologic roles for vitamin D apart from its classic role in bone and mineral metabolism. Specific nuclear receptors for 1xcex1,25-dihydroxyvitamin D3, the hormonally active form of vitamin D, are present in cells from diverse organs not involved in calcium homeostasis. For example, Miller et al., 52 Cancer Res. (1992) 515-520, have demonstrated specific, biologically active receptors for 1xcex1,25-dihydroxyvitamin D3 in the human prostatic carcinoma cell line, LNCaP.
It has been reported that certain vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and are inducers/stimulators of cell differentiation. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1xcex1-hydroxyvitamin D compounds, specifically 1xcex1,25-dihydroxyvitamin D3 and 1xcex1-hydroxyvitamin D3, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. Antiproliferative and differentiating actions of 1xcex1,25-dihydroxyvitamin D3 and other vitamin D3 analogues have been reported with respect to prostate cancer cell lines. More recently, an association between vitamin D receptor gene polymorphism and prostate cancer risk has been reported, suggesting that vitamin D receptors may have a role in the development, and possible treatment, of prostate cancer.
These previous studies have focused exclusively on vitamin D3 compounds. Even though these compounds may indeed be highly effective in promoting differentiation in malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as, for example, antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of 1xcex1,25-dihydroxyvitamin D3 and other vitamin D3 analogues as anticancer agents is precluded, or severely limited, by the risk of hypercalcemia. This indicates a need for compounds with greater specific activity and selectivity of action, i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity. The need for such compounds is no greater than in the treatment of neoplastic and hyperplastic prostatic diseases.
The present invention provides a method of treating prostatic disease conditions such as those characterized by hyperproliferative cell growth and/or abnormal cell differentiation, e.g., prostate cancer and prostatic hyperplasia. The method includes use of active vitamin D compounds to inhibit abnormal cell growth and promote cell differentiation.
The foregoing, and other advantages of the present invention, are realized in one aspect thereof in a method of inhibiting the hyperproliferative activity of human neoplastic or hyperplastic cells, comprising treating the cells with an effective amount of a 1xcex1-hydroxyvitamin D compound having a hydrocarbon moiety substituted at the C-24 position on the sidechain of the molecule. The treating step includes inhibiting proliferation of, and inducing and enhancing differentiation in such prostatic cells.
The 1xcex1-hydroxyvitamin D compound is an active vitamin D and is suitably represented by the formula (I) described hereinafter. Preferred among the compounds of formula (I), are 1xcex1,24-dihydroxyvitamin D2, 1xcex1,24-dihydroxyvitamin D4,1xcex1,25-dihydroxyvitamin D4, 1xcex1,25-dihydroxyvitamin D2,1xcex1-hydroxyvitamin D2 and 1xcex1-hydroxyvitamin D4.
The effective or therapeutic amount of the 1xcex1-hydroxyvitamin D compound administrable in accordance with the present invention to patients in need on a daily basis per kilogram of body weight ranges from 0.01 xcexcg/kg/day to 2.0 xcexcg/kg/day.
In another aspect, the invention is a method of treating human prostate cancer, comprising administering to a male subject who has prostate cancer an effective amount of an active vitamin D compound which has, or attains through metabolism in vivo, a vitamin D receptor (VDR) binding affinity substantially equivalent to the binding affinity of 1xcex1,25-dihydroxyvitamin D3 and a hypercalcemia risk substantially lower than that of 1xcex1,25-dihydroxyvitamin D3, to decrease or stabilize the cellular abnormal proliferative activity of the cancer.
For treatment for prostate conditions in accordance with the present invention, the active vitamin D is suitably administered alone as an active ingredient, i.e., as a first anticancer agent, in a pharmaceutical composition, or in a mixture including a second anticancer agent, an androgen abalation agent, a 5xcex1-reductase inhibitor or combinations thereof.
In another aspect, the invention is a pharmaceutical composition which includes a first anticancer agent which is an active vitamin D compound; an agent selected from the group consisting of (i) a second anticancer agent, (ii) a bone agent, (iii) an androgen ablation agent and (iv) a 5xcex1-reductase inhibitor and combinations thereof; and a physiologically acceptable carrier.
Other advantages and a fuller appreciation of specific adaptations, compositional variations, and physical attributes will be gained upon an examination of the following detailed description of preferred embodiments, taken in conjunction with the appended claims.